The present invention concerns a bicomposite material based on collagen, which is biocompatible, non-toxic and biodegradable, comprising uniquely or mainly a layer forming a collagenic film and a layer forming a fibrous polymer compress or sponge with a high level of porosity.
The material according to the invention can be used in surgery, notably in visceral surgery, and is specifically applied for the simultaneous achievement of hemostasis and prevention of post-surgical adhesion, while promoting the healing of the injured tissue.
Patents FR-A-2 628 634 and U.S. Pat. No. A-5,201,745 (IMEDEX) describe patches for use in visceral surgery made of a biomaterial consisting of two layers of collagen superposed and closely associated, these being a porous adhesive layer of fibrous collagen and a collagen film or collagenic material such as gelatine.
In this type of material, the film seals the membrane or patch and increases mechanical cohesion, also helping to prevent the formation of post-operative adhesions. The porous layer of fibrous collagen notably plays the part of a hemostatic compress.
A double-layered collagenic membrane has been proposed in patent applications EP-A-O 686 402 and WO 96/08277 (COLETICA) with the aim of obtaining anti-adhesive properties.
The collagens and collagenic materials used in such patches or membranes may be obtained from native collagen or from different types of atelocollagens or pepsin-treated collagens, notably type I bovine collagens, and type I, III, III+I and IV human collagens. These collagens can be partly oxidized, for example to increase their adhesive power, and the layer forming the film may include other materials, mixed with the collagenic material, used, for example to strengthen its mechanical resistance and improve its anti-adhesion properties. It is not easy to produce these patches or membranes, however. Indeed, on the one hand it is essential to guarantee an excellent bond between the layer forming the film and the layer forming the fibrous compress, while retaining each layer""s individuality on the other. Also, when the layer of fibrous material is brought into contact with the liquid collagenic material destined to form the film, on contact with the liquid, the collagenic fibres tend to become impregnated so that an excellent bond is indeed obtained between the two layers but it is very difficult to control formation of the film and respect the porosity of the supporting layer.
For this purpose, it has been proposed (FR-A-2 628 634), to pour the collagenic material which is to form the film, onto a layer of fibrous collagen which has first been slightly compressed to limit interpenetration between the two layers.
It has also already been proposed (EP-A-O 686 402) to freeze the porous fibrous layer so that it is hydrated and impermeable and pour the liquid collagenic material destined to form the film onto this layer so as to eliminate interpenetration between the two layers, but this level of prevention of interpenetration gives rise to cohesion defects. The process described also gives rise to a two-layer collagengelatine membrane which has been dried or freeze-dried in one piece, which prevents an impermeable film and a highly porous layer from being formed simultaneously. It is also recommended to compress this membrane.
Hemostatic sponges composed of native bovine collagen are commercially available, as for example Colgen(copyright) (Immuno AG), Pangen(copyright) (Fournier) and Surgicoll(copyright) (Biodynamics); but these are not covered on one side with an impermeable film, acting as a barrier and they have several disadvantages:
i) left in the body, they can generate adhesions;
ii) the blood diffuses through preferential routes in the compress, reducing the area of contact of the collagen with the platelets and consequently the hemostatic effect of the compress;
iii) they no longer have a hemostatic effect on strongly bleeding wounds (ruptured arterioles for example), because the blood passes through the compress;
iv) generally produced from acid collagen, they are difficult to handle because they strongly stick to surgical instruments or latex gloves.
Other more complex products such as TachoComb(copyright) (Nycomed) combining collagen, fibrinogen, thrombin and aprotinin provide better hemostasis than collagen sponges, but these products are likely to facilitate the development of post-operative adhesions. They contain thermolabile enzymes and must be stored between 2 and 8xc2x0 C. The multiplication of components of human or animal origin is also a handicap, because of problems of traceability and registration linked to these products, leading to prohibitive excess cost.
From the point of view of preventing post-operative adhesions, this is particularly difficult with haemorrhagic wounds, especially where bleeding is widespread (Buckman et al., J. Surg. Res., 1976, 20 1-5; Wiseman et al., J. Reprod. Med., 1992, 37, 766-770). Bleeding from wounds strongly affects the efficacy of the products marketed and used to prevent adhesion, such as INTERCEED(copyright) TC7 (Johnson and Johnson) (Wiseman et al., J. Reprod. Med., 1992, 37, 766-770). Indeed it can lead to the deposit of fibrin on the anti-adhesive film and then facilitate the development of post-operative adhesions. This results in the necessity to perform the most complete hemostasis possible, using thrombin or any other technique, before applying products such as INTERCEED(copyright) TC7 to haemorrhagic wounds. Therefore to prevent adhesions it is advantageous to develop materials which also have hemostatic properties.
The present invention therefore aims to considerably perfect the previously described bicomposite collagenic materials, and to improve their hemostatic properties considerably, while retaining and, if necessary, even improving their properties which aim to prevent post-operative adhesions.
The invention also aims to provide a hemostatic bicomposite collagenic material which can, in addition, prevent post-operative adhesions and facilitate healing.
Another of the invention""s aims is to produce such a material which particularly promotes colonization by the body""s specific cells and is likely to be completely biodegradable within a short time and easy to control by making simple changes to the manufacturing process.
The invention also aims to provide a biocompatible bicomposite material which is non-toxic and not sticky to the touch when dry, to facilitate handling, but which can develop adhesive properties in a physiological environment, in particular in contact with blood.
Another of the invention""s aims is to provide a particularly economic process to obtain such a bicomposite material.
Therefore the invention aims to produce a bicomposite collagenic material which is biocompatible, non-toxic and biodegradable in less than a month, characterized in that it comprises solely or principally two closely linked layers, these being a layer forming a film based on a collagenic constituent, notably collagen which has at least partially lost its helical structure, or gelatine, and a layer forming a porous compress, substantially uncompacted, based on a polymer constituent.
As well as the collagenic constituent, the film preferably comprises at least one macromolecular hydrophilic additive which does not react chemically with collagen.
The second layer can be made of a porous compress, substantially uncompacted, of non-denatured collagen.
The invention also aims to provide a preferred process for producing these materials.
This process is based on the discovery that, when a liquid solution based on a collagenic constituent destined to form a film is left to gel, there is an instant, during gelling, when the porous layer of polymer constituent forming the compress can be laid on the surface of the gelling material, and the under part of the said porous layer partly penetrates the gel, while at least partly retaining a structure which guarantees almost perfect adhesion between the film to be constituted and the porous layer, while preserving almost all the individual properties of the porous layer and the film.
The inventors noted most surprisingly that:
the collagen film can be formed by dehydration of the liquid layer of collagen in spite of the presence of a freeze-dried porous layer on top of it;
the upper porous layer is not degraded or changed by association with the film in the process of formation.
The invention therefore aims to provide a process for obtaining a bicomposite material according to the invention, characterized in that a solution of collagenic constituent is poured onto a suitable inert support, to a thickness destined to form a film, and in that a substantially uncompacted compress made of a polymer constituent is applied onto the said solution during gelification, and then in that the material obtained is dried or left to dry.